Protein-protein interactions are an integral component of many sections of this proposal. This DBP focuses on an important family of proteins, the cadherins, whose binding specificity plays a central role in cell-cell adhesion. Our goal is to understand the molecular basis of the binding specificity of cadherins and, in turn, the structural basis of many cell-cell adhesion processes. The fundamental question to be addressed concerns how cadherins are able to bind to one another at the cellular level in a homophilic fashion, even though many cadherins are closely related to one another in sequence, and thus might be expected to cross-react. Indeed heterophilic binding is sometimes observed in in-vitro measurements. In addition, we wish to understand the diverse function of different cadherins and to see how different cadherin subfamilies have evolved to carry out distinct, albeit related functions.